Candidacy for Lung Transplant and Lung Allocation

C a n d i d a c y f o r Lu n g Tr a n s p l a n t a n d Lu n g Allocation Carli Jessica Lehr, MDa,*, David William Zaas, MD, MBAb KEYWORDS
Lung transplantation
Lung allocation score
Age
Critical illness

KEY POINTS
The Lung Allocation Score was developed in 2005 as a multi-variate model for organ allocation with the intention to decrease waiting list mortality and to allocate organs based on medical urgency.
Diagnosis categories (Groups A-D) have been shown to impact both pre- and post-transplant survival.
Patients over the age of 65 and critically ill patients continue to comprise a greater proportion of transplants performed each year.
Further analysis of the outcomes following implementation of the Lung Allocation Score must continue to continue to improve patient outcomes and survival in the post-transplant period.

Lung transplantation has changed greatly since the first lung transplant was performed by J.D. Hardy in 1963 at the University of Mississippi. It took nearly 20 years for the development of cyclosporine to make transplant a viable option for patients with end-stage pulmonary disease.1 Survival rates continued to increase through the 1980s as the number of transplants increased and cyclosporine became more widely used.2 The growth of solid organ transplantation necessitated a national system to provide oversight over organ allocation and transplant outcomes. Congress passed the National Organ Transplant Act (NOTA) in 1984 to direct the development of a national organ transplant registry in an effort to supervise allocation processes and organ matching in the United States.3 After the creation of NOTA, the Organ Procurement and Transplantation Network (OPTN) was created to manage allocation in conjunction with the United Network

for Organ Sharing (UNOS) with the development of the Scientific Registry of Transplant Recipients (SRTR) to examine outcomes. Over the last 50 years, lung transplant outcomes have continued to improve and the lung allocation system has evolved, with a goal to maximize the net benefit provided for all donated lungs.4,5 Before 1995, the allocation process for lungs was solely based on wait-list time, geographic location, and blood type.6 In 1995, a special exemption was made to allow for credit for an additional 90 days for patients with idiopathic pulmonary fibrosis (IPF) given their increased wait-list mortality; however, this did not account for variable mortality among other pulmonary diseases represented on the wait-list. The structure of the wait-list continued to select for patients able to survive for extended periods, because the time to transplant was greater than 2 years for more than half of the transplant list. Each year, the number of inactive candidates increased, to a peak of 2001 inactive candidates in 2005.7

The authors have nothing to disclose. a Department of Internal Medicine, Duke University Hospital and Health System 2301 Erwin Road, Durham, NC 27705, USA; b Department of Medicine, Duke University, 2301 Erwin Road, Durham, NC 27705, USA * Corresponding author. E-mail address: [email protected] Thorac Surg Clin 25 (2015) 1–15 http://dx.doi.org/10.1016/j.thorsurg.2014.09.001 1547-4127/15/$ – see front matter Published by Elsevier Inc.

thoracic.theclinics.com

BACKGROUND

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Jessica Lehr & Zaas The structure of the wait-list led to the practice of listing patients early to provide the greatest chance to survive until transplantation and led to increased allocation for patients with more stable pulmonary disease. In response to the increasing numbers of deaths on the transplant list, the US Department of Health and Human Services instituted the Final Rule in March, 2000, which directed that medical necessity must be included in organ allocation as opposed to wait time alone.8,9 The Lung Allocation Subcommittee was created to devise a new strategy and allocation system to comply with the mandates set forth by the Final Rule. The goals set forth by the Lung Allocation Subcommittee included reduction in mortality on the waiting list, prioritization of candidates based on clinical urgency and avoiding futile transplants, and decreasing the importance of waiting time and geography within the constraints posed by ischemic time.10 The Lung Allocation Score (LAS) was developed as a multivariate model for allocation in an effort to decrease waiting list mortality and to alter the allocation process to provide access to organs to those patients most in need. Numerous studies have evaluated the impact of the changing allocation methodologies on the demographics and outcomes of lung transplantation. Since 1985, the age of recipients has increased from 45 years to 55 years, and after implementation of the LAS, 10% of recipients were older than 65 years and 3% were older than 70 years.11 Chronic obstructive pulmonary disease (COPD) was the leading indication for transplantation from 1995 to 2004, and the proportion of bilateral compared with single-lung transplants

increased for every diagnosis besides cystic fibrosis (CF). Before LAS initiation, survival rates were 86% at 3 months, 76% at 1 year, 49% at 5 years, and 24% at 10 years. Survival rates continued to increase, particularly in the first 3 months after transplantation, attributable to improved operative and improved management of early posttransplant complications. In the analysis of categorical risk factors for 1-year mortality performed by the International Society for Heart and Lung Transplantation (ISHLT) in 2005, specific diseases such as primary pulmonary hypertension (PPH), IPF, and sarcoidosis were found to have greater relative risks for 1 year mortality than any identified donor/recipient or specific transplant characteristics (Table 1).11 The magnitude of diagnosis continued to affect the 5-year mortality, although other continuous variables such as recipient and donor age/body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters), recipient pretransplant bilirubin level, creatinine level, and pulmonary artery systolic pressure also significantly affected the risk of death.11

LUNG ALLOCATION SCORE In 2004, the OPTN approved the revised LAS as a numeric score from 0 to 100 for patients aged 12 and older, which was implemented on May 4, 2005.10 The current LAS is a numeric scoring system developed to rank patients listed for transplant both by expected transplant benefit balanced with risk of death while on the waiting list. The goal of the LAS is to prioritize objective

Table 1 Lung disease diagnosis group classification in the LAS Group A

Group B

Group C

Obstructive lung disease Eisenmenger CF Bronchiectasis syndrome Immune deficiency Sarcoidosis with mean PPH syndromes (common pulmonary artery pressure Pulmonary vascular variable of 30 mm Hg diseases immunodeficiency, Lymphangioleiomyomatosis (thromboembolic hypogammaglobulinemia) a-1-Antitrypsin deficiency disease, veno-occlusive disease) CREST (pulmonary hypertension) Pulmonic stenosis

Group D IPF Sarcoidosis with mean pulmonary artery pressure >30 mm Hg CREST: restrictive Interstitial pneumonias Acute respiratory disease syndrome/ pneumonia Amyloidosis Connective tissue diseases Primary graft failure after lung transplant

Data from OPTN Policy 10.1.F.i. Lung disease diagnosis group classification in the Lung Allocation Score (LAS). p. 125–7.

Lung Allocation clinical data rather than measures of clinical acuity, which can be subjective and often difficult to agree on by clinicians. A key element to the development of an equitable LAS is the comparison between survival with transplantation to survival without transplantation. Because risk of pretransplant mortality varies depending on a patient’s clinical status, it is important to allow alteration of a patient’s score as their clinical condition changes. Another important objective of the algorithm is the estimation of the survival benefit related to transplantation to ensure that this scarce resource would derive the greatest deal of potential benefit to patients. Expected survival time with or without transplant in the score is calculated by measuring the area under a waiting list and 1 year posttransplant survival curves. The waiting list urgency measure is obtained by calculating the expected number of days of life without a transplant during 1 year on a wait-list. The posttransplant survival measure is defined as the expected number of days lived during 1 year after transplant. The waiting list urgency measure is subtracted from the posttransplant survival measure yielding the 1-year transplant survival benefit. It was important to provide an equal weight to both urgency and likelihood of posttransplant survival to ensure that patients in either category did not receive increased weight in the scoring system. The decision to truncate posttransplant survival at 1 year

was made based on the assumption that pretransplant factors affecting survival would have decreasing importance as time increased past 1 year (Fig. 1).10 The LAS is calculated as transplant benefit minus the waiting list urgency measure (posttransplant survival measure minus 2 times the waiting list urgency measure).10 The LAS is calculated as a raw allocation score with values ranging between 1365 to 730, which represent the 2 extremes of 100% 1-year posttransplant survival/death on waiting list and 100% waiting list 1-year survival/death on day 1 after transplant7,12 (OPTN Policy 3.7.6.1.1). This number is normalized to a 0 to 100 scale for ease of clinical application by the formula, 100  (raw score 1 2  365)/(3  365). A multitude of factors were found to be significant predictors of outcome and included in the LAS formula to determine the area under the curve, which comprises the wait-list urgency measure and posttransplant survival measure (Tables 2–4). Before implementation of the LAS, the SRTR created waiting list and posttransplant models to attempt to determine hazard ratios and identify factors that affected survival. Independent risk factors were stratified into hazard models by diagnosis, and these were compared to determine if there was significant variability between alternative diagnoses.13 Allocation scores were then compared using stratified hazards (by diagnosis) versus proportional hazards (independent risk factors) and

Fig. 1. Hypothetical scatterplot of expected waiting list survival versus calculated transplant benefit allocated by both benefit and urgency. Transplant benefit 5 expected transplant survival minus expected wait-list survival. Patients placed lower than the transplant benefit threshold experience a negative benefit from transplant. When weighting this graph equally between urgency and benefit, the angle of the best-fit line approaches 45 . The SRTR performed analyses of different angles, finding similar rates of death under 45 and increased rates of death above 60 , which resulted in adoption of the 45 model outlined earlier. (From Egan TM, Edwards LB, Coke MA, et al. Lung allocation in the United States. In: Lynch JP III, Ross D, editors. Lung and heart-lung transplantation (lung biology in health and disease series). New York: Marcel Dekker Inc; 2006. p. 1222; with permission; and Data from SRTR Analysis, 2004.)

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Table 2 Equations for the calculation of the LAS Formula

Index

LAS 5 100½PTAUC2WLAUC1730 1095 364 P

PTAUC: the area under the posttransplant survival curve (first posttransplant year) WLAUC: the area under the waiting list survival curve (in next year) bi: coefficient for characteristics in the waiting list survival model STX(t): expected posttransplant survival probability for an individual (at time t) Yi: value of the jth characteristic for an individual candidate aRj: coefficient for characteristic j from the posttransplant model SWL,0(t): baseline waiting list survival probability at time t STX,0(t): baseline posttransplant survival probability at time t SWL(t): expected waiting list survival probability for an individual candidate at time t Xi: value of the ith characteristic for an individual candidate

PTAUC 5

STX ðkÞ

k50

STX ðtÞ 5 STX;0 ðtÞexpða1 Y1 1a2 Y2 1/1aq Yq Þ WLAUC 5

364 P

SWL ðkÞ

k50

SWL ðtÞ 5 SWL;0 ðtÞexpðb1 X1 1b2 X2 1/1bp Xp Þ

Data from OPTN Policy 10.1.F. The LAS calculation. p. 124.

were similar.14 Thus, it was decided to use the proportional hazard model for increased simplicity. At the time of LAS implementation, it was determined that transplant centers were required to update clinical data used to calculate the LAS every 6 months. The only variable that may be amended less frequently is right-heart catheterization data in an effort to minimize patient risk.7,8,14 Since conception, the LAS has changed to incorporate both independent hazards in addition to diagnoses, because some diagnoses have independent variables that have greater severity prognostication for that particular disease. Patients are separated into 4 diagnosis groups:

obstructive lung disease (group A), pulmonary vascular disease (group B), CF/immunodeficiency disorders (group C), and restrictive lung disease (group D).4 This grouping was created to assemble diseases by similar clinical and statistical features in an effort to provide adequate weight to diagnoses with sample sizes too small to build diagnosis-specific mortality models.15

ALLOCATION IN ADULTS Lung allocation in adults is based on multiple variables, including the LAS, patient age and blood type, geography, and thoracic cavity size.

Table 3 Factors used in the waiting list mortality calculation: covariates and their coefficients Factors Used in the Waiting List Mortality

Diagnosis Impact on Waiting List Mortality

Age Bilirubin (value, increase of 50%) BMI Cardiac index (before exercise) Central venous pressure (before exercise) Ventilation status Creatinine Diabetes Diagnosis group/specific diagnoses (see Table 1) Forced vital capacity (group D only) Functional status (assistance with activities of daily living) Oxygen requirement (to maintain saturation >80%) PCO2 (40 or increase of 15%) Pulmonary artery pressure (>40 mm Hg) 6-Minute walk distance

Diagnosis group B (1.57) Diagnosis group C (1.23) Sarcoidosis with mean pulmonary artery pressure 30 mm Hg (0.93) Bronchiectasis (0.67) Diagnosis group D (0.63) Obliterative bronchiolitis (0.44) Group A (0) Pulmonary fibrosis (0.21) Lymphangioleiomyomatosis (0.31) Sarcoidosis with mean pulmonary artery pressure >30 mm Hg (0.46) Eisenmenger syndrome (0.63)

Data from OPTN Policy 3.7.6.1.1. Impact factors taken from OPTN Policy 3.7.6.1.1 The LAS Calculation Table 1. p. 88–91.

Lung Allocation

Table 4 Factors used in the posttransplant survival calculation: covariates and their coefficients Factors Used in Posttransplant Survival

Diagnosis Impact on Posttransplant Survival

Age Creatinine (at transplant, increase of 150%) Cardiac index (before exercise) Ventilation status Oxygen requirement (to maintain saturation >80%) 6-Minute walk distance (if < 365 m [1200 ft]) Functional status (assistance with activities of daily living) 6-Minute walk distance

Eisenmenger syndrome (0.92) Diagnosis group B (0.62) Diagnosis group D (0.46) Diagnosis group C (0.36) Bronchiectasis (0.19) Group A (0) Sarcoidosis with mean pulmonary artery pressure >30 mm Hg (0.04) Pulmonary fibrosis (0.07) Sarcoidosis with mean pulmonary artery pressure 30 mm Hg (0.13) Obliterative bronchiolitis (1.21) Lymphangioleiomyomatosis (1.52)

Data from OPTN Policy 3.7.6.1.1. Impact factors taken from OPTN Policy 3.7.6.1.1. The LAS Calculation Table 1. p. 91–3.

Geographic considerations are central to allocation to minimize organ ischemic time, leading to lung offerings first within a geographic zone. According to the OPTN Policy 3.7.10, organ allocation should first occur locally and then extend geographically through predetermined circular zones of 500, 1000, 1500, and 2500 nautical mile radii from the donor center.12 A local zone is within the donation service area (DSA) or the organ procurement organization. The LAS is calculated in patients aged 12 years and older and is also used for allocation of lungs from donors aged 12 years and older. For all adult donor lungs (age 18 years), priority first goes to recipients who are 18 years and older. In donors aged 12 to 17 years, organs are first allocated to ages 12 to 17 years, then pediatric patients (<12 years), and then, adult recipients. For donors aged 12 years and younger, lungs are first prioritized by time waiting and then priority goes first to recipients younger than 12 years, because of difficulty finding a suitable size match, then, 12 to 17 years, and then, recipients who are 18 years and older. The allocation of organs based on age group has created many ethical concerns in patient families, the media, and those in the transplant community. Since 1985, a few adult recipients have received organs from pediatric donors (age 0–11 years), and the number of adult recipients receiving preadolescent organs has remained stable at around 10%.11 The mortality of children on the waiting list is similar to that for adolescents and adults, although the donor pool is smaller than for older recipients.16 Children aged 0 to 11 years are not included in the LAS system, and a high LAS does not increase their priority to receive adult

lungs, although the use of partial lobar transplants had been successful in pediatric patients. In this situation, the organs are offered to all acceptable candidates aged 12 years and older in the region. This protocol has prompted practice-changing legislation, allowing patients like Sarah Murnaghan and Javier Acosta, pediatric patients with endstage CF, to be considered for listing on the adult lung transplant list on a case-by-case basis with the OPTN review board. These recent changes in legislation allow select patients younger than the age of 12 years to be considered for evaluation by LAS and allow for eligibility for adult lungs or lobar transplants based on their disease severity. In addition, it has been proposed that the donor pool be expanded by changing legislation to increase priority for access to adolescent donors to pediatric recipients.16,17

ALLOCATION IN ADOLESCENTS (AGES 12–17 YEARS) Allocation in adolescents (aged 12–17 years) is similar to that in the adult population, with the exception that available donor organs are first offered to adolescent candidates. Further allocation is similar to adults, with geographic preference first to local candidates who are ABO identical and then to local candidates who are ABO compatible. If no candidates are identified, preference then goes to child recipients (<12 years). Donor lungs are offered to local adult candidates only if there are no suitable local adolescent or child recipients. The recipient range is then expanded to the same zones, A, B, C, D, and E, as are used in adult organ allocation.4,12

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Jessica Lehr & Zaas ALLOCATION IN CHILDREN YOUNGER THAN 12 YEARS Children are grouped together from ages 0 to 11 years in the lung allocation schema, and transplantation is not governed by the LAS. At the time of LAS development, children were not included, because the impact of diagnoses had the potential to make the LAS a poor prognostic indicator for severity of disease and required transplant urgency. Children are designated as either priority 1 or priority 2, depending on meeting a specific set of predetermined criteria. To become priority 1 status, a candidate must have 1 or more of the following: respiratory failure, pulmonary hypertension, or an exception case reviewed by the Lung Review Board12 (OPTN Policy 3.7.6.2) (Box 1). Preference is given to patients in priority 1 based on ABO compatibility followed by contiguous time spent as priority 1 status. Multiple episodes of priority 1 status cannot be combined to increase waiting time, although it is contributory in situations in which there is a tie between priority 1 candidates. Ties are determined based on total waiting time, which is defined as the summation of time spent as priority 1, priority 2, and inactive time12 (OPTN Policy 3.7.9.3). The ranking of

Box 1 Determination of priority 1 child candidates Candidates must have one of the following:
Respiratory failure  Requiring continuous mechanical ventilation or  Requiring supplemental oxygen to sustain FiO2 greater than 50% to maintain oxygen saturation levels greater than 90% or  Arterial/capillary PCO2 greater than 50 mm Hg, or a venous PCO2 greater than 56 mm Hg
Pulmonary hypertension  Stenosis of pulmonary veins involving 3 or more vessels  Showing suprasystemic pulmonary artery pressure on cardiac catheterization or echocardiogram  Cardiac index less than 2 L/min/m2  Syncope  Hemoptysis Data from OPTN Policy 3.7.6.2. Candidates Aged 0–11. p. 106–7.

priority 2 candidates is determined by total waiting time, and clinical data must be updated every 6 months to maintain priority 1 status on the waiting list. Candidates maintain their priority 2 status if they are identified as requiring an organ by their transplant center. Donor organs in children younger than 12 years first are allocated to ABO identical priority 1 pediatric recipients within the local DSA, zone A, and zone B combined. If no recipients are found, then, priority 1 ABO compatible donors from the same geographic area are selected, followed by priority 2 candidates. Donor lungs are then offered successively to adolescent ABO identical candidates from DSA and zone A, adult ABO identical candidates from DSA and zone A, adult ABO compatible candidates from DSA and zone A. If no suitable candidates are identified in the DSA and zone A, priority then moves to adolescents in zone B, then, adults in zone B, and then, to children in zone C. If there are still no suitable matches, the net is cast wider to include first adolescents in zone C, followed by adults in zone C, and to zones D and E4,12 (OPTN Policy 3.7.11).

CHANGES TO THE LUNG ALLOCATION SCORE SINCE CONCEPTION The first alteration to the LAS came in 2008, when the PCO2 value was incorporated into the LAS calculation after analysis indicating that PCO2 values affected wait-list mortality and posttransplant survival outcomes.18 The LAS incorporates both current PCO2 and change in PCO2 measured by the threshold change ([highest PCO2–lowest PCO2]/lowest PCO2) and threshold change maintenance ([current PCO2–lowest PCO2]/lowest PCO2). The threshold change evaluates if the change in PCO2 is greater than 15% and the threshold change maintenance is an additional value that the candidate receives after the impact from the threshold change. This value determines the candidate’s ability to benefit from the impact given to the LAS from the threshold change12 (OPTN Policy 3.7.6.1.3). The addition of bilirubin to the LAS also came in 2008, although the logistics of implementation have progressed slowly. Bilirubin measurements make little difference for most transplant candidates but have a high impact factor for some candidates with idiopathic pulmonary hypertension (group B). In group B patients, an increase in bilirubin level of greater than 50% from time of listing increases risk of death while on the waiting list.19 As in PCO2 measurements, bilirubin levels are measured by current bilirubin and change in bilirubin, which is accounted for by 2 change

Lung Allocation calculations: threshold change ([highest bilirubin– lowest bilirubin]/lowest bilirubin) and threshold change maintenance ([current bilirubin–lowest bilirubin]/lowest bilirubin). Additional changes include the removal of forced vital capacity (FVC) in all groups except group D diagnoses, because this did not have statistical significance in the revised waiting list model. There have also been minor changes related to the weighting of factors within the model. The last changes made to the LAS were in 2012, and further changes are anticipated as more factors affecting mortality are studied and tested within the current model.20 In addition, as data continues to be analyzed through large-scale descriptive studies such as REVEAL registry (Registry to Evaluate Early and Longterm Pulmonary Arterial Hypertension Disease Management) and the Lung Retrospective Data Collection Projects, it is expected that more data will become available to continue to adapt the model as the characteristics of patients on the waiting list continue to evolve.20,21

PRIMARY DIAGNOSIS AND EFFECT ON LUNG ALLOCATION SCORE Patients on the waiting list had vastly different survival times, and the implications of diagnosis on wait-list mortality were thoroughly investigated before implementation of the LAS. The 4 primary diagnoses taken into consideration include COPD, idiopathic pulmonary arterial hypertension (IPAH), CF, and IPF. Based on data in the OPTN/SRTR

database from 2001 to 2002, mortality on the wait-list was 9.7%, 13.1%, 17.8%, and 23.1% for group A, B, C, and D diagnostic groups, respectively.13 Each of these diseases has different risk factors associated with increased patient mortality. Patients with low wait-list mortality, such as those with COPD, had a greater chance of survival to transplantation with the system before the LAS. Development of the LAS greatly affected the impact of diagnostic grouping on likelihood of transplant (Fig. 2).

GROUP A: CHRONIC OBSTRUCTIVE PULMONARY DISEASE COPD accounted for a total of 14,784 lung transplants from January, 1995 to June, 2012. Before the implementation of the LAS, COPD (both A1ATD [Alpha-1 anti-trypsin deficiency] and nonA1ATD) represented most lung transplants performed. COPD comprised 35.4% of transplants from 1990 to 2004, with a decrease to 30.9% of transplants after 2005, although non-A1ATD COPD decreased from 40% to 30%.13 The preLAS allocation system led to increased transplant in patients with COPD given their high survival rates at 80% and 70% at 2 and 3 years after listing.22 In patients with COPD, factors contributing to waiting list mortality included hospitalization, steroid dependency, FEV1, O2 requirement at rest, BMI, and age.8,10,13,23 The factors contributing to the 1-year posttransplant mortality included hospitalization at time of transplant, age, and center

Fig. 2. Indications for transplant by diagnosis (before LAS compared to after LAS). (Adapted from Yusen RD, Christie JD, Edwards LB, ISHLT. The Registry of the International Society for Heart and Lung Transplantation: thirtieth adult lung and heart-lung transplant report–2013; Focus theme: age. J Heart Lung Transplant 2013;32(10):965–78; with permission.)

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Jessica Lehr & Zaas volume.8,10,13 In a study published in the American Journal of Transplantation in 2009 by Titman and colleagues,22 a survival benefit was identified in patients with COPD, although it was less than in other diagnostic groupings, which was also supported by 2 earlier European studies.24,25 Median survival is 5.4 years and average conditional median survival for patients surviving to 1 year after transplantation is 6.9 years in non-A1ATD and 8.7 years in those with ATATD-related COPD. Patients with COPD have the lowest unadjusted 3-month mortality, of 9% after transplantation.7,13 However, the implementation of the LAS had a significant impact on the indications for transplant. The percentage of patients with COPD continues to decline slowly after implementation of the LAS, and IPF has surpassed COPD as the most prevalent transplant diagnosis.

GROUP B: IDIOPATHIC PULMONARY HYPERTENSION Based on data compiled in the REVEAL registry, for patients enrolled between 2006 and 2009, the 1-year, 3-year, and 5-year survival in patients with pulmonary arterial hypertension were 85%, 68%, and 57%.26,27 The cause of death in most patients is progressive right-sided heart failure and combined heart-lung transplant (HLT) and double-lung transplant has been associated with improved long-term outcomes when compared with single-lung transplant in IPAH.28 IPAH has accounted for a total of 1160 lung transplants since 1995.7 Factors contributing to waiting list mortality in this group include hospitalization, mechanical ventilation, steroid dependency, and wedge pressure, with risk factors for posttransplant mortality of intensive care unit (ICU) status, single-lung transplant, and increased BMI.7,10,23 Group B patients make up 5.1% of the waiting list, a decrease from 8.3%, and the average wait time is 9.7 months.7 Based on the most recent ISHLT data from 2013, the median survival of patients with IPAH with lung transplant is 5.2 years, with a conditional median survival for patients surviving the first year of 10.0 years.13,28 Patients with IPAH made up 23% of HLT recipients from June, 2000 to June, 2012 and survival after HLT has improved, particularly in the early posttransplant period. Survival for all-comers was 63% at 1 year, 44% at 5 years, and 31% at 10 years; however, patients who survived the first year after HLT had a median survival of 3.3 years and a conditional median survival of 10 years, which did not differ among pretransplant diagnoses.11 A retrospective study performed by Schaffer and colleagues29 comparing lung transplantation in the

pre-LAS and post-LAS eras found a statistically significant increase in the incidence of transplantation as well as decreased wait-list mortality in patients with IPAH in the post-LAS era.11 An additional study performed by Chen and colleagues30 found an increased likelihood of transplantation and an unchanged wait-list mortality, without a change in posttransplant mortality. Higher cardiac index is an independent predictor for improvement in survival in patients with IPAH and is an important component to the LAS in this patient population.28 The addition of bilirubin to the LAS also benefits patients with IPAH, because this can be a surrogate marker for hepatic congestion caused by worsening right-heart function. Although the number of patients listed on the waiting list who went to transplant increased after implementation of the LAS, IPAH represented a decreased percentage of all organ recipients (5.8% before the LAS, and 3.2% after LAS), raising the concern that the LAS may not adequately assign priority to this patient population.28,30 As of 2011, group B candidates made up 5.1% of the waiting list and have a median wait time of 9.7 months.7 Patients with IPAH also have the highest unadjusted 3-month mortality at 22%, although average survival after transplantation is 10 years.11 The implementation in the LAS coincided with increasing use of improved end-stage pulmonary hypertension therapies, such as inhaled iloprost and oral sildenafil. Sildenafil was approved by the US Food and Drug Administration for use in pulmonary hypertension in 2005 after it was studied in multiple trials showing improvement in World Health Organization functional class, exercise capacity, and hemodynamics.31–33 In addition, inhaled iloprost was approved in 2004 for severe pulmonary hypertension.33,34 It is difficult to ascertain whether improved wait-list survival and decreased transplantation is caused by LAS implementation or by improved pharmacologic therapies. Since that time, additional therapies in the categories of prostacyclin analogues, phosphodiesterase 5 inhibitors, endothelin receptor antagonists, and soluble guanylate cyclase stimulators have entered the market, significantly affecting the treatment of severe pulmonary hypertension. The most recent study by Schaffer and colleagues29 indicated a dramatic improvement in the incidence of transplantation, with reduced wait-list mortality for end-stage patients, many of whom are refractory to advanced medical therapies. In addition, these investigators found a survival advantage associated with listing at medium-volume to high-volume centers that was postulated to be caused by access to advanced IPAH therapies.

Lung Allocation GROUP C: CYSTIC FIBROSIS The 2013 report of the ISHLT indicates that patients with CF make up the third largest diagnosis group undergoing transplant: 16.3% of all lung transplants performed in the last 15 years, with a median survival of 7.8 years, with a conditional median survival of 10.5 years.11,35,36 Predictors for waiting list mortality include hospitalization, steroid dependency, diabetes, wedge pressure, FVC % predicted, cardiac output, and BMI, with posttransplant mortality risk factors of drugrelated peptic ulcer disease before listing.7,10,23 Adoption of the LAS did not change the percentage of transplants for CF. Thabut and colleagues37 performed a study published in 2013 evaluating survival benefit of lung transplant for patients with CF after the implementation of the LAS. In their study cohort of 704 adult patients with CF, they found that 39.3% received a transplant at 3 months, 64.7% at 12 months, with death rates while on the wait list of 8.5% and 12.9%, respectively. Survival after transplant was 96.5% at 3 months, 88.4% at 12 months, and 67.8% at 3 years. The investigators found that lung transplant decreased the risk of death by 69% in their cohort. This study used the LAS as a proxy for patient severity on the waiting list and found that a higher LAS was associated with a statistically significant increase in survival benefit for lung transplant.37 Before this study, 9 studies assessed the survival benefit of lung transplant in patients with CF, with mixed results.35

GROUP D: IDIOPATHIC PULMONARY FIBROSIS Lung transplant has been shown to improve both survival and quality of life in patients with severe interstitial lung disease (ILD) that is refractory to medical therapy.38 After transplantation for IPF, patients have a median survival of 4.5 years, with a conditional median survival of 7 years, similar to group A and B diagnoses.11 The survival time may in addition be affected by the increased age of diagnosis compared with patients with CF. Historically, patients with IPF have been poor candidates for transplant, given their advanced age and multiple comorbidities. Before the implementation of the LAS, patients with IPF experienced the highest death rate while on the waiting list for transplantation when compared with CF and COPD.8,39 Risk factors for waiting list mortality in patients with IPF include hospitalization, mechanical ventilation, steroid dependency, and wedge pressure, with posttransplant mortality risk factors including ICU status, single-lung transplant, and higher BMI.7,10,23 As IPF progresses, the

development of pulmonary hypertension significantly increases the risk for posttransplant pulmonary complications and decreased survival.40 A study performed by De Oliveira and colleagues41 showed that patients with IPF after 2005 had a higher LAS of 43.3 compared with those before 2005, with an average LAS of 38.3 without increased rates of postoperative mortality, and also noted that the waiting list time decreased from 266 days before LAS to a mere 78 days in the post-LAS transplant model. The investigators also found that patients in the post-LAS era are not only transplanted more frequently, representing 27.4% of transplants compared with 17.3%, but also are older, require increasing amounts of supplemental oxygen before transplant, and have lower cardiac indices.41 After the advent of the LAS, patients with IPF made up 12% of waiting list recipients, a 6% decrease from the previous year, representative of the increase in IPF transplants to 28% from 24% in just 1 year.39 In the most recently published 2011 OPTN/SRTR Annual Data Report, group D made up 46.1% of waiting list candidates, with a median waiting time of only 2.1 months.7 Although patients with IPF make up a significant number of lung transplant recipients, they have documented decreased posttransplant survival, particularly in the early posttransplant period, compared with other indications for lung transplant.42

AGE IN TRANSPLANT There are many transplant centers that continue to use an age cutoff of 65 years for transplant eligibility, because advanced age in transplant recipients has been identified as a risk factor for increased posttransplant mortality.13 Patients older than 55 years begin to experience an increased 1-year mortality, which increases with age. However, patients older than 65 years have similar rates of diabetes, hypertension, acute rejection, and renal dysfunction compared with younger patients, although they experience an increased incidence of skin cancers.11 Many proponents of increasing eligibility for older recipients dispute the validity of chronologic age compared with the importance of functional age in posttransplant outcomes. After implementation of the LAS in 2005, the subgroup of recipients aged 65 years and older have increased most rapidly.43 Patients aged 65 and older comprised less than 5% of transplant recipients in 2002 and increased to 19% in 2008 and 26.6% in 2011.7,11,44 A consensus report published by the ISHLT in 200645 recommended that age older than 65

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Jessica Lehr & Zaas years should serve as a relative contraindication to lung transplant based on registry data indicating reduced survival in this age cohort. The ISHLT 30th Adult Lung and Heart-Lung Transplant report indicated a median survival of 3.6 years in patients older than 65 years, compared with 6.5 years in those aged 35 to 49 years, with a 5-year survival of 38% for patients older than 65 years, 46% for those 60 to 65 years, and 52% to 57% for patients younger than age 60 years.11 Two studies published after implementation of the LAS reported no difference in both 1-year and 3-year survival rates compared with younger patient cohorts.46,47 A retrospective cohort study was performed by Genao and colleagues43 evaluating 4805 patients who received a lung transplant between 2005 and 2009, stratifying patients by age 65 years or older compared with those younger than 65 years. Functional status was measured by Karnofsky performance score (KPS) before and after transplantation, and investigators found that older age was not associated with different rates of decline in KPS over time and that the rate of functional decline was not greater in patients aged 70 years and older compared with age 65 to 69 years. A recent study performed by Kilic and colleagues48 evaluated the outcomes of lung transplantation in patients older than 70 years after implementation of the LAS in 2005 and found that outcomes in patients 70 years and older are comparable with outcomes in those aged 65 to 69 years. The most recently published OPTN/SRTR Annual Data Report from 2011 indicates that candidates older than 65 years continue to be added faster than any other age group and comprise 24.4% of the waiting list, a

stark change from a mere 2.9% of candidates in 1998 (Fig. 3).7

DISPARITIES IN TRANSPLANT Racial disparities in lung transplantation have improved with the introduction of the LAS, although gender disparities have increased.49 Wille and colleagues49 performed a study of 8806 registered waiting list patients and found that black patients were less likely to undergo transplantation before LAS compared with white recipients (56.3% vs 69.2%; odds ratio [OR] 0.54; P<.001), which improved in the LAS era (86% vs 87%; OR 1.07, P 5 .74). The percentage of female lung transplants also decreased to 41.9% in 2011 compared with 53.5% in 2001, which may be caused by a decreased number of female donors.7 Women had an increased likelihood of death or critical illness precluding transplant compared with men after implementation of the LAS (16.1% vs 11.3%; OR 1.58, P<.001) compared with the pre-LAS system (33.4% vs 30.7%; OR 1.19, P 5 .08).49 To our knowledge, no studies have been performed that address other racial or ethnic groups that aid in the understanding of unintended consequences caused by the LAS system. Given the focus of geographic regions in the LAS, it is important to consider the potential for geographic disparities when comparing the preLAS and post-LAS eras. Before implementation of the LAS, listing and lung transplantation was shown to be reduced for patients living in rural areas without a transplant center in close proximity.50 A study performed by Thabut and colleagues50 indicated that the LAS did not diminish

Fig. 3. Age in transplant. (Adapted from Yusen RD, Christie JD, Edwards LB, ISHLT. The Registry of the International Society for Heart and Lung Transplantation: thirtieth adult lung and heart-lung transplant report–2013; Focus theme: age. J Heart Lung Transplant 2013;32(10):965–78; with permission.)

Lung Allocation these geographic disparities. However, this study did not identify decreased transplantation rates or clinical follow-up once patients were listed. This study was unable to identify if these disparities were caused by reduced rural referral rates, reduced listing, or personal preference of patients in these remote locations. Furthermore, improvements to the current allocation system to mitigate geographic disparities in transplant listing will be an important consideration as further modifications are made to the LAS.

CRITICAL ILLNESS BEFORE TRANSPLANT Before the development of the LAS in 2005, critically ill patients were at a significant disadvantage, because the primary determinant for transplant was time spent on the waiting list.51 Critically ill patients have historically contributed to approximately 10% of deaths on the waiting list. Although the LAS model incorporates both the risk of 1-year wait-list mortality and 1-year posttransplant survival, wait-list mortality carries a greater weight in the algorithm.10 There has been debate after implementation of the LAS as to the effect of the score on survival as well ass studies showing increased ICU time and greater rates of primary graft dysfunction.52 A study was performed by Russo and colleagues53 to address the association between the LAS at time of transplantation and postoperative morbidity and mortality. This study grouped 3386 patients into LAS of less than 50 (n 5 3161), LAS 50 to 75 (n 5 411), and LAS greater than 75 (n 5 197), with a primary outcome of posttransplant graft survival at 1 year and secondary outcomes of in-hospital complications and length of stay. The study found that LAS greater than 75 was associated with significantly decreased survival in the first year (proportion alive 0.82 in LAS >75 compared with 0.89–0.93 in LAS <75) and increased complications during the transplant hospitalization; however, there was no difference between LAS in the incidence rate of death during years 1 to 3 after transplant.53 The rate of change in LAS is also critical to posttransplant survival, and a study from Tsuang and colleagues54 reported that 702 patients with a change in LAS greater than 5 had a significantly worse posttransplant survival (hazard ratio 1.31; 95% CI 1.11–1.54), even when adjusted for LAS at time of transplantation. In patients with an LAS greater than 50, a program must update the status of assisted ventilation, supplemental oxygen, and current PCO2 every 14 days to ensure the most accurate clinical data.20 Historically, extracorporeal membrane oxygenation (ECMO) as a bridging strategy to lung transplantation has been associated with poor

outcomes.55–57 As technology continues to improve, outcomes continue to improve as ECMO patients are becoming ambulatory and managed with minimal sedation.58,59 A recent study performed by Fuehner and colleagues60 compared 26 patients bridged to lung transplant with 34 historical control patients receiving invasive mechanical ventilation with a significant survival advantage in the awake ECMO group, of 80% versus 50%. A study performed by Turner and colleagues58 focusing on incorporation of rehabilitation and physical therapy in 3 patients awaiting transplantation on ECMO reported positive posttransplant outcomes, with all patients being weaned from the ventilator and becoming ambulatory within 1 week after transplant. Although ECMO is not yet the standard of care before transplantation, it provides a valuable strategy for patients who would otherwise be unable to survive to transplant. These patients have survival that is comparable with and often improved compared with traditional mechanical ventilation, with further improvement expected as awake and ambulatory ECMO begin to emerge as standards of care in ECMO bridging protocols. Malnutrition in critically ill patients significantly increases posttransplant morbidity and mortality. In a study of 453 patients undergoing lung transplantation, performed by Chamogeorgakis and colleagues,61 9% to 25% of patients carried a diagnosis of malnutrition defined by a BMI less than 18.5, weight/height ratio 0.3 or less, albumin less than 3.5 g/dL, total protein less than 6 g/dL, and an absolute lymphocyte count less than 1000. In this study, the investigators found that hypoalbuminemia (<3 g/dL) was associated with increased 1 year posttransplant mortality.61 A UNOS study performed by Allen and colleagues62 assessed the effect of BMI on posttransplant outcomes in 11,411 patients, with evidence of increased risk of death with patients who are both under weight and over weight.

CURRENT IMPLICATIONS AND FURTHER DIRECTIONS FOR ALLOCATION In the years after the LAS, the number of transplants continues to increase, with 1830 lung transplants performed in 2011, 70.1% bilateral and 29.9% single-lung transplants, and 3.8% retransplants. The wait-list number continues to increase, with 2200 new candidates added to the list in 2011, and donation rates have been unable to match the increasing demand. Donation rates have continued to increase over the past 10 years, with the largest contribution from donors aged 15 to 34 years, with an increase from 7.4 to 13.7

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Jessica Lehr & Zaas donations per 100 deaths over the past 10 years.7 The decrease in inactive candidates on the waiting list since implementation of the LAS suggests that patients are being listed at an optimal time and that the transplant process may be occurring more efficiently. The proportion of patients who receive a lung transplant within 1 year of listing is on average 64.4%, although this varies significantly based on the DSA.7 The median LAS at transplantation continues to increase: 40.8 in 2011 with 6.3% of wait-listed patients with an LAS of greater than 50 compared with 36.6 in 2005 with less than 2% of wait-listed patients with an LAS greater than 50. A critical issue in the current algorithm is the increased weight given to pretransplant mortality, which may promote allocation of scarce organs to patients with low posttransplant mortality. In the study by Russo and colleagues,53 patients with LAS from 90 to 100 and 80 to 90 had an expected survival of only 1.56 and 2.28 years, respectively. According to the most recent OPTN/SRTR 2011 annual report, the incidence of primary graft failure decreased to 5.3% and decreased longterm graft failure. This report delineated a clear relationship between worsening LAS and decreased graft survival.7 These findings have led many to suggest the possibility for alternative transplantation strategies for patients with extremely high scores. For example, in heart transplantation, risk of posttransplant mortality higher than a defined level leads to reduction of transplantation priority or placement on an alternative transplant list.63 This strategy could permit high-risk recipients to receive only organs that are not suitable for standard recipients in an effort to extract the greatest benefit from the scarce resource of donated organs. Further study is needed regarding addition of other prognostic factors in the 4 diagnostic groupings to provide the most equitable ranking system based on disease-specific markers of clinical severity. Results of studies analyzing posttransplant survival after LAS are conflicting, with a study performed by Kozower and colleagues52 from 2008 identifying increased incidence of primary graft dysfunction and longer ICU stay in the postLAS era, although there was similar 1-year survival. A study performed by McCue and colleagues64 found no difference in posttransplant morbidity and a small, although statistically significant, 1-year survival advantage in the post-LAS era. A review article by Hachem and colleagues65 presented data from UNOS indicating a largely unchanged survival rate, with a 2-year survival of 72.23% in patients transplanted between 2000

and 2005 compared with a 2-year survival of 70.14% in patients transplanted between 2005 and 2006.7 Promising data in the most recent publication by ISHLT in 2013 indicate that from 1988 to 2011, the 1-year survival improved from 70% (1988–1994) to 81% (2004–2011). In a KaplanMeier survival analysis performed by ISHLT in 2005 for transplants performed between 1994 and 2003, mean survival was 4.8 years for COPD, PPH 4.3 years, CF 5.8 years, and IPF 3.7 years. This finding can be compared with ISHLT KaplanMeier survival analysis from 201311 documenting patients with transplants performed between 1990 and 2011 with 5.4 years for COPD, IPAH 5.2 years, CF 7.6 years, and ILD 4.5 years. Wait-list times have continued to decrease since 2005 for diagnosis groups B, C, and D (9.7, 3.7, and 2.1 months, respectively), with an unchanged time to transplant in group A (7.0 months). In 2004, transplant rates per 100 patient years on the waiting list for group A, B, C, and D were 34.1, 7.0, 35.5, and 34.8, respectively, whereas in 2011, these increased across all groups, with rates in group A, B, C, and D of 66.3, 46.9, 119.5, and 165.9, respectively. Mortality in the first year after transplant continues to improve with each passing year, and in 2011, 1-year mortality was 14%, a significant decrease from 23% in 2001. Initially, waiting list mortality improved after the implementation of the LAS, but these are increasing, with a mortality of 15.7 per 100 wait-list years, which may be a reflection of transplantation of critically ill patients with increasing age representation in the waiting list population.7 The LAS fundamentally changed the landscape of lung transplant. The main goals of LAS implementation were to decrease wait-list mortality, decrease waiting time, and improve posttransplant survival rates. Although it is yet to be seen what the long-term sequelae are from this change, reports indicate that survival after transplantation continues to improve for each disease class and that both critically ill and older patients are receiving transplants more frequently. The LAS will continue to evolve as additional data arise regarding disease-specific parameters that are predictive for better and worse outcomes.

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44. Yusen R, Shearon TH, Qian Y, et al. Lung transplantation in the United States, 1999–2008. Am J Transplant 2010;10(4 Pt 2):1047–68. 45. Trulock EP, Edwards LB, Taylor DO, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-second official adult lung and heart-lung transplant report—2005. J Heart Lung Transplant 2005;24(8):956–67. 46. Mahidhara R, Bastani S, Ross DJ, et al. Lung transplantation in older patients? J Thorac Cardiovasc Surg 2008;135(2):412–20. 47. Vadnerkar A, Toyoda Y, Crespo M, et al. Age-specific complications among lung transplant recipients 60 years and older. J Heart Lung Transplant 2011; 30(3):273–81. 48. Kilic A, Merlo CA, Conte JV, et al. Lung transplantation in patients 70 years old or older: have outcomes changed after implementation of the lung allocation score? J Thorac Cardiovasc Surg 2012;144(5):1133–8. 49. Wille KM, Harrington KF, Deandrade JA, et al. Disparities in lung transplantation before and after introduction of the lung allocation score. J Heart Lung Transplant 2013;32(7):684–92. 50. Thabut G, Munson J, Haynes K, et al. Geographic disparities in access to lung transplantation before and after implementation of the lung allocation score. Am J Transplant 2012;12(11):3085–93. 51. Organ Procurement and Transplantation Network. Available at: http://optn.transplant.hrsa.gov. Accessed January 29, 2014. 52. Kozower BD, Meyers BG, Smith MA, et al. The impact of the lung allocation score on short-term transplantation outcomes: a multicenter study. J Thorac Cardiovasc Surg 2008;135(1):166–71. 53. Russo MJ, Iribarne A, Hong KN, et al. High lung allocation score is associated with increased morbidity and mortality following transplantation. Chest 2010; 137(3):651–7. 54. Tsuang WM, Vock DM, Copeland CA, et al. An acute change in lung allocation score and survival after lung transplantation: a cohort study. Ann Intern Med 2013;158(9):650–7. 55. Jackson A, Cropper A, Pye R, et al. Use of extracorporeal membrane oxygenation as a bridge to primary lung transplant: 3 consecutive, successful cases and a review of the literature. J Heart Lung Transplant 2008;27(3):348–52. 56. Nosotti M, Rosso L, Palleschi A, et al. Bridge to lung transplantation by venovenous extracorporeal membrane oxygenation: a lesson learned on the first four cases. Transplant Proc 2010;42(4):1259–61. 57. Olsson K, Simon A, Strueber M, et al. Extracorporeal membrane oxygenation in nonintubated patients as bridge to lung transplantation. Am J Transplant 2010;10(9):2173–8. 58. Turner DA, Cheifetz IM, Rehder KJ, et al. Active rehabilitation and physical therapy during

Lung Allocation extracorporeal membrane oxygenation while awaiting lung transplantation: a practical approach. Crit Care Med 2011;39(12):2593–8. 59. Rehder KJ, Turner DA, Hartwig MG, et al. Active rehabilitation during extracorporeal membrane oxygenation as a bridge to lung transplantation. Respir Care 2013;58(8):1291–8. 60. Fuehner T, Kuehn C, Hadem J, et al. Extracorporeal membrane oxygenation in awake patients as bridge to lung transplantation. Am J Respir Crit Care Med 2012;185(7):763–8. 61. Chamogeorgakis T, Mason DP, Murthy SC, et al. Impact of nutritional state on lung transplant outcomes. J Heart Lung Transplant 2013;32(7): 693–700.

62. Allen JG, Arnaoutakis GJ, Weiss ES, et al. The impact of recipient body mass index on survival after lung transplantation. J Heart Lung Transplant 2010;29(9):1026–33. 63. Felker G, Hernandez AF, Rogers JG, et al. Cardiac transplantation at Duke UniversityMedical Center. Clin Transpl 2003;18:235–41. 64. McCue JD, Mooney J, Quail J, et al. Ninety-day mortality and major complications are not affected by use of lung allocation score. J Heart Lung Transplant 2008;27(2):192–6. 65. Hachem RR, Trulock EP. The new lung allocation system and its impact on waitlist characteristics and post-transplant outcomes. Semin Thorac Cardiovasc Surg 2008;20(2):139–42. Elsevier. WB Saunders.

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